It is known that the chemical synthesis of aromatic imines (or Schiff bases) can generally be achieved by means of the condensation between primary amines and carbonylic compounds (cf. Patai, The Chemistry of Carbon—Nitrogen Double Bond; Wiley: New York, 1970, pp. 64).
Likewise, polysubstituted pyrrol rings can be chemically synthesized in different ways by employing linear or convergent synthesis methodologies (cf. Sundberg, Comprehensive Heterocyclic Chemistry; Katrizki, A. and Rees, C. W. Eds.; Pergamon: Oxford, 1984; vol. 4, pp. 313). One sufficiently general way consists of the aromatization of substituted pyrrolidines (cf. Fejes et al. Tetrahedron 2000, vol. 56, pp. 8545; Gupta et al. Synth. Commun. 1998, vol. 28, pp. 3151). The final heterocycles can be prepared, in turn, by means of the 1,3-dipolar reaction between azomethine ylides and electronically deficient alkenes (cf. Ayerbe et al. J. Org. Chem. 1998, vol. 63, pp. 1795; Vivanco et al. J. Am. Chem. Soc. 2000, vol. 122, pp. 6078).
Methods also abound for the synthesis of indoles (cf. Horton et al. Chem. Rev. 2003, vol. 103, pp. 893), one of which is a convergent procedure described in literature consisting of the thermal cyclation between primary arylamines and haloacetopheonone derivatives (cf. Nyerges et al. Tetrahedron Lett. 2005, vol. 46, pp. 377). However, the yields obtained by this method are not usually very high, due mainly to the relatively high temperatures and the lengthy reaction times necessary for completing the cyclation reaction and the ease with which the reagents may degrade under these conditions.
Oxidative stress facilitates carcinogenesis (Engel R H, Evens A M. Oxidative stress and apoptosis: a new treatment paradigm in cancer. Front Biosci. 2006; 11:300-12) and the prometastatic and proangiogenic mechanisms of cancer (Tanaka T, Akatsuka S, Ozeki M, Shirase T, Hiai H, Toyokuni S. Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis. Oncogene. 2004; 23:3980-9) and many other diseases (Casetta I, Govoni V, Granieri E. stress, antioxidants and neurodegenerative diseases. Curr Pharm Des. 2005; 11(16):2033-52; Sukkar S G, Rossi E. Oxidative stress and nutritional prevention in autoimmune rheumatic diseases. Autoimmun Rev. 2004; 3:199-206; Naito Y, Takano H, Yoshikawa T. Oxidative stress-related molecules as a therapeutic target for inflammatory and allergic diseases. Curr Drug Targets Inflamm Allergy. 2005; 4:511-5.). Thus, numerous cancer research studies have focused their attention on the effects of some natural antioxidant compounds (resveratrol, quercetin, vitamin C, etc.) as chemopreventive agents of carcinogenesis and metastasis. In come cases, it has been proven that said action is caused not solely by means of the antioxidant effect of said agents, but also by way of their action of blocking cyclooxygenases (COX) and tyrosine kinases.
On the other hand, the mechanism of action of most of the proinflammatory and prometastatic factors is regulated by oxygen-reactive metabolites. In this regard, it has been proven that treating animals with catalase prior to their being intrasplenically inoculated with B16 melanoma cells reduces the onset of hepatic metastasis, which indicates that hydrogen peroxide (H2O2), released in response to hepatic colonization by tumor cells, has prometastatic effects (cf. Anasagasti et al., “Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen—4-mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice”. Hepatology. 1997, vol. 25 pp. 840-6).
Trans-stilbene compounds, particularly trans-resveratrol, are widespread throughout nature, mainly in the form of phytoalexins and are attracting growing interest due to a wide range of biological activities useful in oncology, such as the inhibition of carcinogenesis (cf. Jang et al., Science 1997, vol. 275, pp. 218; Gosslan et al., Brit. J. Cancer. 2005, vol. 92, pp. 513) and apoptosis induction (cf. Lee et al., Life Sci. 2004, vol. 75, pp. 2829). This biological activity has been attributed to the antioxidant properties (cf. Stivala et al., J. Biol. Chem. 2001, vol. 276, pp. 22586) and anti-inflammatory properties (cf. Kimura et al., Biochim. Biophys. Acta 1985, vol. 834, pp. 275) of these compounds, as a result of which they can serve as chemopreventive and chemotherapeutic agents (cf. De Lédinghen et al., Int. J. Oncol. 2001, vol. 19, pp. 83; Scheneider et al., Nutr. Cancer 2001, vol. 39, pp. 102; Mahyer-Roemer et al., Int. J. Cancer 2001, vol. 94, pp. 615). It is known that trans-stilbenes are able to isomerize the cis-form which is either inactive or less active. For example, trans-resveratrol can isomerize under the effect of sunlight to convert partially into the cis isomer (cf. F. Olalla, Curr. Med. Chem. 2006, vol 13, pp. 87-98; 1. Kolouchová-Hanzliková et al. Food Chem. 2004, vol. 87, pp. 151-158).